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RESEARCH Open Access

The efficacy of probiotics for monosodiumglutamate-induced obesity: dietology concernsand opportunities for preventionOleksandr A Savcheniuk1, Oleksandr V Virchenko1, Tetyana M Falalyeyeva1, Tetyana V Beregova1, Lidia P Babenko2,Liudmyla M Lazarenko2, Olga M Demchenko3, Rostyslav V Bubnov2,4* and Mykola Ya Spivak2,3

Abstract

Introduction: Obesity becomes endemic today. Monosodium glutamate was proved as obesogenic food additive.Probiotics are discussed to impact on obesity development.

Aims and objectives: The aim was to study the effects of probiotics on the development of monosodiumglutamate (MSG)-induced obesity in rats.

Material and methods: We included 45 Wistar male rats and divided into three groups (n = 15). Newborn rats ofgroup 1 (control) received subcutaneously 8 μl/g saline. Group 2 received 3 to 4 mg/g MSG subcutaneously on thesecond, fourth, sixth, eighth and tenth day of life. Within 4 months after birth, rats were on a standard diet. Group 3received an aqueous solution of probiotics mixture (2:1:1 Lactobacillus casei IMVB-7280, Bifidobacterium animalis VKL,B. animalis VKB) at the dose of 5 × 109 CFU/kg (50 mg/kg) intragastrically. Administration of probiotics was startedat the age of 4 weeks just after weaning and continued for 3 months during 2-week courses. Group 2 receivedintragastrically 2.5 ml/kg water. Organometric and biochemical parameters in all groups of rats were analyzed over4 months. The concentration of adiponectin was determined in serum, and leptin - in adipose tissue.

Results: Administration of MSG led to the development of obesity in rats; body weight had increased by 7.9% vscontrols (p < 0.05); body length had increased by 5.4% (p < 0.05). Body mass index and Lee index and visceral fatmass had increased (p < 0.001). Under the neonatal injection of MSG, the concentration of total cholesterol,triglycerides, VLDL cholesterol and LDL cholesterol significantly increased (p < 0.001), in comparison with controls.Adipose-derived hormones changed in MSG obesity rats: adiponectin decreased by 58.8% (p < 0.01), and leptinconcentration in adipose tissue had increased by 74.7% (p < 0.01). The probiotic therapy of rats from group 3 preventedobesity development. Parameters of rats treated with probiotic mixture did not differ from that in the control.

Conclusions: The introduction of MSG to newborn rats caused the obesity in adulthood. Periodic administration ofprobiotic mixture to rat injected with MSG neonatally resulted in recovery of lipid metabolism and prevention of theobesity development.

Keywords: Predictive, Preventive, Personalized medicine, Obesity, Probiotics, Animal model, Monosodium glutamate,Food additives, Personalized dietology

* Correspondence: [email protected] Institute of Microbiology and Virology, National Academy ofSciences of Ukraine, Zabolotny Str., 154, Kyiv 03680, Ukraine4Clinical Hospital ‘Pheophania’ of State Affairs Department, Zabolotny str., 21,Kyiv 03680, UkraineFull list of author information is available at the end of the article

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OverviewPredictive, preventive and personalized anti-obesity concernsMetabolism is an essential process for the maintenanceof life and homeostasis of the organism. Diseases associ-ated with metabolic disorders such as hyperlipidemia,diabetes and obesity have become extremely common[1,2]. Today, obesity becomes endemic; about 1.7 bil-lion people on the planet are overweight. World HealthOrganization (WHO) has declared obesity a global epi-demic and took it under control [1]. Overweight andobesity cause the leading severe diseases, namely, dia-betes mellitus type 2, cardiovascular diseases (CVD)and breast cancer [3]. The permanently growing cohortof patients with obesity-related diseases, as diabetes,requires the urgent change paradigm from interven-tional measures to predictive, preventive and personal-ized medicine (PPPM) [4,5].Metabolic disturbances in obesity causes a number

of diseases, namely, cardiovascular diseases (hypertension,atherosclerosis, coronary heart disease), stroke, insulin-dependent diabetes, premature death, diseases of musculo-skeletal system (osteochondrosis and metabolic-dystrophicarthritis), hepatobiliary disease (gallbladder dyskinesia,chronic cholecystitis, cholelithiasis) and number oftumor sites, including lung cancer, breast cancer, uter-ine cancer and ovarian; in women, there is a violation ofovarian-menstrual cycle dyslipidemia. Obesity reduceslife expectancy by 3 to 5 and, sometimes, in severe forms,for 15 years [6,7].Health and disease of individuals and of populations

are the result of three groups of factors: genetics, en-vironment and behavior. Only the latter is mostlydependent by the choices of the single person, but as-sessment, interventions and tailored changes are pos-sible [8]. Many of the researchers attribute this to aviolation of the diet. The nature of nutrition today is aserious concern; a growing consumption of ‘fast food’,accompanied by a decrease in the proportion of thedaily diet of vegetables, fruits, milk and dairy productsseriously affects the health. The application of foodsupplement for metabolic syndrome was consideredfor PPPM in [9].The recent data, regarding women’s differential responses

to lifestyle changes, support another branch of researchwith a gender nutrition emphasis within predictive, pre-ventive and personalized medicine [10].Over the past 10 years, morbidity diseases of the gastro-

intestinal tract in children and adults have increased. In2011, in Ukraine, 7,089,010 patients were diagnosed withgastroenterological diseases, per 100,000 of the adultpopulation, 18956.3. At the end of 2011, the recordswere 5,028,034 patients with diseases of the digestiveorgans, i.e. 70.9% of the total registered. In 2006, therewas an increased prevalence of 11.2% [11].

Monosodium glutamateMonosodium glutamate (MSG, C5H8NO4Na, E 621) iswidely distributed and is naturally occurring in variousfoods (bouillon cubes, meat tenderizers, canned food,frozen food, potato and snack chips, barbecue sauce,salad dressing, soups, fast food, etc.) [12].Obesogenic properties of monosodium glutamate were

studied for decades [13,14]. Hirata et al. demonstrated thatMSG obese rats develop insulin resistance to peripheralglucose uptake [15]. MSG induces hyperinsulinemiain 3-month-old rats; the obesity of MSG animals is ametabolic alteration characterized by an enhanced adipo-cyte capacity to transport glucose and to synthetize lipidsresulting in increased insulin sensitivity [16]. It was sup-posed that the central lesions produced by MSG treatmentdisrupt the regulation of the hypothalamic-pituitary-adrenalaxis as the hyperfunctional state of adrenals revealed signsof MSG-treated rats [17].In Ukraine, monosodium glutamate became a legal food

additive (flavour boosters) only in 2000 after the Resolutionof Cabinet of Ministers of Ukraine no. 342 on February 17,2000 ‘Amendments to the list of food additives authorizedfor use in foodstuffs’ [18], which authorized the list of foodadditives in Ukraine.Now, it is hard to find industrially produced canned or

semi-finished products that do not include MSG. Thus,the permissible limits may be significantly exceeded,which can lead to diseases of the digestive tract.

ProbioticsTherefore, the search of new non-toxic means of theobesity prevention is the urgent challenge of modern sci-ence. Today, the question of the probiotics influence onlipid metabolism and obesity is actively debated in thescientific literature [19-21]. Backhed et al. were the pio-neers in the study of the role of colon microflora in themetabolism regulation [22]. Their findings were theimpetus for the research in this field. Further studies haveshown the alteration of intestinal microbiota compositionin overweight people. Thus, intestine microbiocenosis canbe considered the environmental factor that modulatesthe development of obesity.It was demonstrated that prolonged exposure to a high

fat diet significantly changed the composition of thecolon microflora in mice having reduced the level ofBifidobacterium and Lactobacillus that are known toproduce many positive physiological effects, e.g. improvingthe barrier function of the intestinal mucosa and havingincreased levels of Firmicutes and Proteobacteria, whichproduce a lot of toxic substances [23,24].It was found that the oligofructose prebiotic which is a

supplement to a high fat diet resulted in the recovery ofthe normal composition of bifidoflora, hence eliminationendotoxemia and reduction of the obesity development.


These data suggest that bifidoflora may reduce intestinalpermeability and the level of circulating endotoxin. Inaddition, the growth of bifidobacteria improved the sensi-tivity to glucose and decreased the body weight gain andproduction of pro-inflammatory mediators [25-27].Recently, the beneficial effects of probiotic bacteria on

the obesity development was established. For example,the use of Lactobacillus gasseri SBT2055 and Lactobacillusparacasei SSP paracasei F19 prevented the developmentof diet-induced obesity [27,28]. The most important causeof obesity is the excessive consumption of fat and easilydigestible carbohydrates, but due to accumulated data, sci-entists believe that the uncontrolled use of food additivessuch as MSG taste enhancer can also lead to obesity [29].The aim was to investigate the effect of probiotics on

the development of experimental obesity in rats inducedby monosodium glutamate.

MethodsWe included 45 Wistar male rats and divided to threegroups of 15 animals each. Newborn rats of group 1(control) were injected with saline with a volume of8 μl/g subcutaneously on the second, fourth, sixth,eighth and tenth day of life. Newborn rats of groups 2and 3 were administered with MSG dissolved in salineat the dose 4 mg/g of body weight with a volume of8 μl/g subcutaneously on the second, fourth, sixth, eighthand tenth day of life [30].Within 4 months after birth, rats were on a standard

diet. Group 3 received an aqueous solution of a mixtureof probiotics (2:1:1 Lactobacillus casei IMVB-7280,Bifidobacterium animalis VKL, B. animalis VKB) at adose of 5 × 109 CFU/kg (50 mg/kg) intragastrically (i.g.).Group 2 received water with a volume of 2.5 ml/kg i.g.,respectively.Group 2 respectively received 2.5 ml/kg of water

(intragastrically). Administration of probiotics was startedat the age of 4 weeks just after weaning and continuedfor 3 months, intermittently alternating 2-week course ofintroduction with 2-week course of break. The changes inbody weight in all groups of rats were analyzed for 4months from birth. Four-month-aged animals weresacrificed. The rats’ blood was collected in tubes, andvisceral adipose tissue was removed and weighed. Bodylength was measured; body mass index (BMI) (the ratioof body weight (g) of rats to the square of the bodylength (cm2)) and Lee obesity index (the ratio of 1/4 ofcube root of body weight (g) to body nose-to-anus length(cm)) were calculated.Blood samples were kept at a temperature of 38°C for

at least 30 min and centrifuged for 10 min at 1,000 × g,followed by collecting of serum. The concentration ofadiponectin was determined in serum, and leptin wasmeasured in adipose tissue by enzyme immunoassay.

Adipose tissue was homogenized in the TEC buffer(10 mM TRIS, 1 mM EDTA, 250 mM saccharose, proteaseinhibitors (2.5 μg/ml leupeptin, 3.5 μg/ml aprotinin,1 mM phenylmethanesulfonyl fluoride), 1% triton X-100)at the rate of 4 ml buffer per 1 g of tissue. Homogenatewas centrifuged for 15 min, and then medium layer(soluble fraction) was harvested. Cholesterol, triglycerides,high-density lipoproteins (HDL cholesterol), low-densitylipoproteins (LDL cholesterol), very low-density lipopro-teins (VLDL cholesterol), bilirubin, activity of alanine andaspartate aminotransferase in serum were determinedby standard biochemical methods. All investigated param-eters of all rats were estimated in the same material whichis serum, except leptin which was measured in visceraladipose tissue. The concentration of leptin and adiponectinwas measured with immunoassay method using ‘BioVendor’commercial kits (Czech Republic) (Leptin Mouse/Rat Elisa,Adiponectin HMW Mouse/Rat ELISA).Research was conducted in compliance with the

standards of the Convention on Bioethics of the Councilof Europe’s ‘Europe Convention for the Protection ofVertebrate Animals’ used for experimental and otherscientific purposes’ (1997), the general ethical principlesof animal experiments, approved by the First NationalCongress on Bioethics Ukraine (September 2001) andother international agreements and national legislationin this field. Animals were kept in a vivarium that wasaccredited in accordance with the ‘standard rules onordering, equipment and maintenance of experimentalbiological clinics (vivarium)’. Instruments to be usedfor research are subject to metrological control.Statistical analysis of data was carried out by the software

package ‘Statistica 8.0’. For the analysis of data distributiontype, Shapiro-Wilks criterion was used. As the datawere normally distributed, we used Levan criterion forevaluating the equality of variance and Student’s t testfor independent samples. We calculated mean values(M) and standard deviations (SD). Significant differencewas considered at p ≤ 0.05.

ResultsAdministration of MSG in the neonatal period leads tothe development of obesity in 4-month-old rats. Table 1shows the organopometric parameters in three groupsof rats. It was found that after 4 months in animalsinjected with MSG, body weight was significantly higherin comparison with control animals by 7.9% (p < 0.05).This decreased the body length in the group of rats withexperimental obesity by 5.4% (p < 0.05). Body length ingroup 2 was decreased by MSG introduction by 5.4%(p < 0.05) compared to that of the control. The calculationof body mass index and Lee index suggested the devel-opment of obesity in group 2. The significant increaseof visceral adipose tissue mass was also observed in animals

Table 1 Organopometric parameters of glutamate-induced obesity rats and corrected parameters by probiotics

Intact rats (n = 15) MSG-induced obesity р1 р2 р3

Placebo (n = 15) Probiotic blends (n = 15)

Weight, g 241.9 ± 25.5 261 ± 17.8 256.7 ± 27.7 0.016 >0.05 >0.05

Body length, cm 21.4 ± 0.9 20.3 ± 1.6 21.5 ± 0.6 0.023 >0.05 0.011

Body mass index 0.53 ± 0.05 0.64 ± 0.08 0.56 ± 0.07 0.002 >0.05 >0.05

Lee index 0.29 ± 0.01 0.32 ± 0.02 0.30 ± 0.01 0.013 >0.05 >0.05

Visceral fat mass, g 2.53 ± 0.78 17.31 ± 5.69 10.65 ± 3.89 <0.001 <0.001 <0.001

Data are presented as the M ± SD. p1, group 1 vs group 2; p2, group 1 vs group 3; p3, group 2 vs group 3. Significant p value < 0.05.


injected with MSG by 583% (p < 0.001) in comparison withthat of the control. These data confirm the findings that theintroduction of glutamate sodium to newborn rodents in-duces the development of visceral obesity in adult animalsand is a model of obesity in rodents [30].While the development of MSG-induced obesity was

registered, there were no functional changes in the liver.It was confirmed by determination of bilirubin and albu-min concentration and activity of alanine and aspartateaminotransferase in blood serum (Table 2). However, inthe blood of animals, injected with MSG, the lipid me-tabolism changes that are characteristic of the metabolicsyndrome are observed. Under the neonatal injectionof MSG, the concentration of total cholesterol, triglyc-erides, VLDL cholesterol and LDL cholesterol significantlyincreased by 55% (p < 0.001), 210% (p < 0.001), 210%(p < 0.001) and 83% (p < 0.001), respectively, comparedto those of the controls (Table 3). Also, it was found thatMSG introduction influenced HDL cholesterol concentra-tion; it decreased by 33.1% (p < 0.001).Taking into account the literature data that adipose

tissue is an active secretory organ and can model thedevelopment of obesity, we have investigated the con-tents of adipose-derived hormones in rats of all groups.Analysis of the secretory function of adipose tissue showeda change in the concentration of adipose-derived hor-mones in rats with experimental obesity caused byMSG. Thus, the level of adiponectin in the serum of ratswith monosodium glutamate-induced obesity decreasedby 2.43 times (p < 0.01).These results are confirmed by the literature data,

which shows the low levels of adiponectin in humans

Table 2 Biochemical indicators of liver in blood serum of glut

Intact rats (n = 15)

Placebo (n

Alanine aminotransferase, μkat/L 0.228 ± 0.033 0.211 ± 0.031

Aspartate transaminase, μkat/L 0.389 ± 0.034 0.377 ± 0.041

Total albumin, μmol/L 12.4 ± 2.09 12.7 ± 1.53

Indirect bilirubin, μmol/L 7.9 ± 1.7 8.1 ± 1.06

Direct bilirubin, mmol/L 4.4 ± 0.91 4.6 ± 0.91

Data are presented as the M ± SD. p1, group 1 vs group 2; p2, group 1 vs group 3; p

with obesity and insulin resistance. A study on rhesusmonkeys, which simulated obesity and type 2 diabetes,confirmed this statement and showed that adiponectinlevels decreased in parallel with the progression of datapathological conditions [31,32]. Scherer Lab set a line oftransgenic mice with a threefold increase in adiponectinlevels in serum [33]. For this model, hyperadiponectinemiacharacteristically increased the sensitivity of peripheraltissues to insulin by improving carbohydrate and lipidmetabolism associated with increased activation of AMPKin the liver and the expression of peroxisome proliferator-activated receptor-gamma (PPARγ) in visceral adiposetissue. These animals are resistant to the development ofinsulin resistance induced by intake of a high fat diet [34].Treatment of animals with recombinant adiponectin

with obesity leads to decreased hyperglycemia and freefatty acids (FFA) in plasma and improves insulin sensitivity[35]. Activation of PPARγ in vivo leads to increased adipo-nectin levels [36]. In mice without adiponectin, hepaticinsulin resistance was observed in parallel with a decreasein therapeutic response to agonists of PPARγ, indicatingthat adiponectin is an important factor enhancing PPARγ-mediated improvement in insulin sensitivity [37].The physiological function of leptin is to prevent obesity

in excessive flow of food into the body. Reduced leptin se-cretion during fasting is a kind of signal to increase energyabsorption. When there is excessive consumption of food,there will be increased activation of thermogenesis energyfor the formation of brown fat by inducing the expressionof genes responsible for the synthesis of mitochondrialproteins of type 1, 2 and 3; severe oxidative phosphoryl-ation occurs, regulating the rate of thermogenesis in the

amate-induced obesity rats and corrected by probiotics

MSG-induced obesity р1 р2 р3

= 15) Probiotic blends (n = 15)

0.221 ± 0.034 >0.05 >0.05 >0.05

0.392 ± 0.044 >0.05 >0.05 >0.05

12.3 ± 1.98 >0.05 >0.05 >0.05

7.7 ± 1.4 >0.05 >0.05 >0.05

4.6 ± 0.97 >0.05 >0.05 >0.05

3, group 2 vs group 3. Significant p value < 0.05.

Table 3 Biochemical parameters of lipid metabolism in serum of glutamate-induced obesity rats and correctedby probiotics

Intact rats (n = 15) MSG-induced obesity р1 р2 р3

Placebo (n = 15) Probiotic blends (n = 15)

Triglycerides, mmol/L 1.15 ± 0.27 3.53 ± 0.57 2.91 ± 0.72 <0.001 <0.05 >0.05

Total cholesterol, mmol/L 4.53 ± 0.34 7.04 ± 0.26 4.72 ± 0.37 <0.001 >005 <0.001

Very low-density lipoproteins, mmol/L 0.51 ± 0.12 1.58 ± 0.26 1.07 ± 0.41 <0.001 <0.05 <0.05

HDL cholesterol, mmol/L 1.63 ± 0.14 1.09 ± 0.19 1.37 ± 0.11 <0.001 <0.05 <0.05

LDL cholesterol, mmol/L 2.37 ± 0.22 4.35 ± 0.29 3.02 ± 0.49 <0.001 <0.05 <0.05

Data are presented as the M ± SD. p1, group 1 vs group 2; p2, group 1 vs group 3; p3, group 2 vs group 3. Significant p value < 0.05.


body [38]. Analysis of the concentration of leptin in adiposetissue in rats that were administered in the neonatal mono-sodium glutamate showed an increase in this indicator by74.7% (p < 0.01) compared to that of the intact animals(Figure 1). With obesity, serum leptin resistance increasesdue to the central hypothalamic action and lipocytokinemechanisms for negative feedback or defect transportthrough the blood–brain barrier. However, the effect ofleptin on peripheral tissues preserved, so we can suspectthe presence of selective leptin resistance. Tissues to leptinresistance develop gradually, activating the growth of adi-pose tissue [38]. It has been shown that the introductionof MSG causes lesions in the arches and ventromedialnuclei of the hypothalamus, causing insensitivity to leptinand insulin in this region resulting in developing hyperlep-tinemia and hyperinsulinemia [39].Probiotic therapy performed to animals that received

MSG (4 mg/g) at 2, 4, 6, 8 and 10 days of life preventedthe development of obesity in rats. Thus, in rats injectedwith probiotic mixture, there is increased body lengthby 6.1% (p < 0.05) compared to that of the placebo andnot different from that of the intact controls. Proof of

Figure 1 Concentration of adipose-derived hormones. (A) Concentratioadipose tissue of rats with glutamate-induced obesity and corrected by prodouble number signs (##), p < 0.01 in comparison with group 2.

reducing obesity index was significantly reduced Leeindex and visceral fat mass.Probiotic consumption also increased the adiponectin

level, decreased the leptin concentration in adipose tissueand restored the anthropometric parameters and lipidmetabolism (Tables 1 and 3; Figure 1). Such results areconsistent with other studies and show effectiveness ofprobiotics in obesity prevention.Periodic administration of probiotics led to restoration

of lipid metabolism in rats. The probiotic strains haveinfluenced the cholesterol concentration, which has beenrestored to the level of control. In organism of animals,injected with probiotic strains, the VLDL cholesterolconcentration decreased by 32.3% (p < 0.05), LDL choles-terol by 30.6% (p < 0.05) and HDL cholesterol increasedby 25.7% (p < 0.05) compared with those of the group 2.These values did not reach the level of control (Table 2).Probiotics introduction led to the normal hormonal activityof adipose tissue.Thus, intermittent administration of probiotics, namely

for 2 weeks, resulted in increased adiponectin levels,decreased leptin concentrations in adipose tissue and

n of adiponectin in serum (mkg/ml) and (B) concentration of leptin inbiotics; double asterisks (**), p < 0.01 in comparison with group 1;


recovery of bodymetric parameters and lipid metabol-ism in animals that were injected with monosodiumglutamate as neonates. The results show the effectivenessof probiotic therapy to prevent obesity, consistent withother studies.

Study limitationThe survey was conducted on animals. We administeredMSG subcutaneously (8 ml/g); however, consideringthat MSG is a food additive, the per os administration(with mother milk for newborn animals) would be mostpreferable for the relevant modeling. The study didnot consider an immunology, genetic, cellular regulationmechanisms, obesity-related conditions, namely diabetes,gout, autoimmunity, and many factors of obesogenicenvironment and other issues that may impact to obesitydevelopment. Research itself did not suppose the predict-ive and personalized approaches.

DiscussionAs the current research did not touch regulation mecha-nisms of obesity and related conditions, namely diabetes,gout, autoimmunity and many factors of obesogenic en-vironment and other issues that impact to obesity devel-opment, we consider to overview the series of importantobesity-associated topics, the impact of probiotics to theobesogenic environment to crystallize the predictive andpersonalized approaches in the field. Many mechanismsof obesity are still unclear; new pathways are still awaitedand insufficiently studied and should be extensively ana-lyzed in conjoint paradigm. We hope that the discussionof the following issues for deeper understanding of cer-tain mechanisms of obesity for effective translation re-sults into real PPPM practice.

Intestinal microbiota and obesityThe gut microbiota can be considered an extension of theself and, together with the genetic makeup, determines thephysiology of an organism, metabolism and obesity [40].Strachan [41] described the hygiene hypothesis that refers toan originally associated reduced microbial contact to mi-crobes in early life and is suggested to be one of the mainmechanisms to account for the increasing prevalence ofallergic diseases over the past few decades. Today, reducedmicrobial exposures (and the rise in allergic conditions)have been attributed to Western lifestyle factors such asdiet, antibiotic use, vaccinations, reduced household sizeand improved hygiene [42]. Recently, probiotic bacteriahave been tested for their ability to affect obesity.Previously, it was shown that the decrease of the choles-

terol concentration in mice with high fat diet causedhypercholesterolemia under the influence of Lactobacillusта Bifidobacterium, especially L. acidophilus ІМВ В-7279,B. animalis VKB and B. animalis VKL [43].

The probiotic Lactobacillus gasseri SBT2055 was ableto reduce adiposity and body weight in obese adults con-suming a fermented milk with the bacterium for 12 weeks,potentially by reducing lipid absorption and inflammatorystatus [44]. A study by Luoto et al. [45] showed the effectof perinatal Lactobacillus rhamnosus GG on childhoodgrowth patterns; the probiotic modulated the body weightincrease in the early life but had no effect in later stagesof development.A recent study demonstrated that Lactobacillus paracasei

ssp paracasei F19 prevented diet-induced obesity in mice[46]. Lactoferrin (LF), a multifunctional glycoprotein inmammalian milk, is reported to exert a modulatory effecton lipid metabolism and improve visceral fat-type obesity,an underlying cause of the metabolic syndrome. Using adouble-blind, placebo-controlled design, a study involvedJapanese men and women (n = 26; aged 22 to 60 years)with abdominal obesity [47]. From these results, eLFappears to be a promising agent for the control ofvisceral fat accumulation with no adverse effects withregard to blood lipid or biochemical parameters.Therefore, influence of probiotics on obesity is activelydebated, and we were the first who showed the prevent-ive influence of the probiotic treatment in rat modelwith MSG-induced obesity.However, the use of probiotics has several drawbacks;

namely, introduction of foreign microorganisms induceantagonistic activity against pathogenic and indigenousmicroorganisms, and eliminating fast the probiotic strain.Therefore, to achieve the personalized approach, thedevelopment and application products manufacturedfrom own strains of organism seem promising. For thisreason, certain individual microorganisms might be grownon artificial nutrient, exploring their environment friendli-ness, establish spectrum antagonistic effects on the body.The potential alternative for probiotics might be the sug-gested lysates of probiotic strains that also exhibit immu-nomodulatory activity.

Obesity genetics: monogenetic vs polygenetic conceptFor over a decade, obesity genetics has been predominantlydriven by research into monogenic or syndromic obesity.Obesity tends to cluster within families and is more

closely correlated between mono- and dizygotic twins.Studies of twins suggested that 80% of the risk of obesityis conveyed by genetic factors [48]. Some individuals aremore predisposed than others to obesity-associateddiseases, but it is presently difficult to identify the ‘atrisk’ individuals who would benefit the most from indi-vidualized monitoring and care [49].In the 1960s, Neel proposed the ‘thrifty gene’ hypothesis

[50], whereby genes that predispose to obesity would havehad a selective advantage in populations that frequentlyexperienced starvation.


Recently, it was described a kinase suppressor of Ras 2(ksr2), an intracellular scaffolding protein involved inmultiple signaling pathways [49]. Targeted deletion ofksr2 leads to obesity in mice, suggesting a role in energyhomeostasis as highly efficient in conserving energy. Theexpression of genes mediating oxidative phosphorylationis also downregulated in the adipose tissue of ksr2(−/−)mice [49]. This ‘hunger gene’ (ksr2) may cause continuedhunger pangs in patients who are obese, as well as slowtheir metabolism. People who possess these genes in today’sobesogenic environment might be not just slightly over-weight but becoming extremely obese [49]. These observa-tions and our in vitro findings suggest that pharmacologicalapproaches based on the modulation of KSR2 activity couldrepresent a novel potential therapeutic strategy for thetreatment of obesity and type 2 diabetes.

Rare familiar obesityRare familiar obesity include the pure forms of obesity,where the gene defect is in appetite regulation, and thedisease is characterized by severe early onset obesitybecause of hyperphagia; syndromic forms have providedadditional insights into the mechanisms underlyingobesity [51,52]. Thus, cloning of the mouse ob gene andits human homologue, leptin [51], proved a paradigm ofmany genes involved in the regulation of appetite viathe leptin-melanocortin pathway including leptin andits receptor, the α-melanocortin-stimulating hormonereceptor (MC4R), pro-opiomelanocortin (POMC) andprohormone convertase-1 [52].

Polygenic obesityThe human obesity gene map [52,53] accumulated inthe field of common polygenic obesity, 253 quantitativetrait loci (QTLs) identified in 61 genome-wide scansand 52 genomic regions. There are currently 22 gene as-sociations supported by positive studies [52-54]. Thesegenes include members of the leptin-melanocortinpathway, pro-inflammatory cytokines and uncouplingproteins. The largest numbers of studies have been car-ried out on ADRB2 and PPARG, but the fact that theyalso have reported associations with asthma and T2D,respectively, may account for this [52]. The TCF7L2association with diabetes demonstrate that sufficientlypowerful studies can generate statistically strong results(p < 10−8) [54].In both rare and common forms of obesity, that

epigenetic influences, defined as any heritable influenceon genes that occurs without a change in the DNA se-quence, are also important, as the rare Prader-Williand Angelman syndromes due to variations in genomicimprinting at the proximal long arm of chromosome15 [52,55], gender-related differential responses relatedto obesity development [10].

Panel of biomarkers for assessing obesity andassociated disordersIt is promising to develop biomarkers, fed through dif-ferent techniques, applicable to minimize the incidenceof obesity and related disorders, and the morbidity andmortality it causes, leading to improve prevention andclinical management strategies. If well-characterizedbiomarkers were available, therapeutic intervention toprevent or delay the onset of obesity or its complica-tions in susceptible individuals might become possible[56]. In addition, biomarkers might help us separatedifferent sub-types of obesity, including those most as-sociated with diabetes, cardiovascular disease and cancer.Some are prospective biomarkers for these different statesof health and disease [57-60].

Oxidative stress and obesityOxidative stress (OS) has been postulated as one of themain physiopathological hallmarks of most of chronicdiseases, primarily neurodegenerative diseases, such asAlzheimer’s disease and other dementias, Parkinson’sdisease, amyotrophic lateral sclerosis, epilepsy and multiplesclerosis [61,62], arthritis, cardiac dysfunctions and dis-eases that cause irreversible blindness, diabetic retinop-athy, macular and retinal degeneration. Lastly, aging ofany body is also associated with oxidative stress becausethe activity of the natural antioxidant system declineswith age and the concentration of lipid peroxidationproducts increases.Keaney and colleagues [63] report that smoking, diabetes

and obesity are independently associated with increasedoxidative stress in men and women in a large community-based cohort. Thus, the pro-inflammatory and pro-oxidanteffects of increased adiposity represent a potential linkbetween obesity and cardiovascular diseases.There was an expressed idea that obesity is a state of

chronic oxidative stress and inflammation. Oxidativestress induced by reactive oxygen species (ROS) is oneof the main factors in cellular aging and many cellulardisorders, which cause extensive damage to DNA [64];also in mitochondria, it is an interesting promoting factorin virus-initiated carcinogenesis, metabolism and in-flammation. In inflammation, ROS and nitric oxide(NO), generated by inflammatory cells, play a key rolein carcinogenesis. Thus, ROS can induce the formationof 8-oxodG, an indicator of oxidative DNA damage, andNO, the formation of 8-nitroguanine, a marker of nitrativeDNA damage. These factors are potentially mutagenicwhich may account for the cancer-promoting effect ofinflammation. While therapeutic treatments cannot bebased exclusively on the abatement of oxidative stress,neutralizing this cellular disorder could minimize col-lateral damages associated with the transformation ofbiomolecules in the cytosol.


Toxic visceral fatExcess intra-abdominal adiposity has the potential to influ-ence metabolism and cardiometabolic risk directly throughalterations in the secretion of adipokines. Abdominal obes-ity promotes increased secretion of a range of metabolitesand of biologically active substances, including glycerol,FFA, inflammatory mediators (e.g. tumor necrosis factoralpha (TNFα) and interleukin-6 (IL-6)), plasminogen activa-tor inhibitor-1 (PAI-1) and C-reactive protein [65-67].

Cardiovascular diseasesObesity is well known to increase the risk of develop-ment of cardiovascular diseases. The evidence suggestedan increase in the risk of ischemic heart disease associ-ated with elevated plasma FFA (top vs lowest tertile)after correction for non-lipid risk factors, although furthermultivariate adjustment for lipid parameters and insulinweakened the association [67]. The majority of circulatingFFA originates from upper-body subcutaneous adipocytes,whereas intra-abdominal fat content has been positivelycorrelated with splanchnic FFA levels which may contributeto the liver fat accumulation commonly found in abdominalobesity [68,69].Adiponectin has been shown to have many favorable

metabolic properties [31-37]. The low adiponectin levelshave been associated with adverse cardiovascular outcomes[65]. The secretion of adiponectin, an apparently cardiopro-tective adipokine, has been shown to be reduced in abdom-inally obese patients [68]. Leptin is an adipokine involved inthe regulation of satiety and energy intake [38,39,65-69];levels of leptin in the plasma increase during the develop-ment of obesity and decline during weight loss.Cardiovascular diseases are strongly connected to im-

mune response. Pathogenesis of cardiovascular diseases isassociated with dysfunction of cytokine production. In mostautoimmune diseases observed, stereotyped response in theform of a large subpopulation of activated Th1 lymphocytes[70], not rarely observed, decrease in the number of Tlymphocytes, impaired T helpers/suppressors ratio down-ward suppressor activity, weakening the response to themitogens. In patients with autoimmune disease, frequentincreased levels of pro-inflammatory cytokines (TNF-α,IL-1, IFN-γ) may result in aberrant activation of the innateimmune response [71]. During a persistent heart muscledamage, the exposure of the intracellular content to deadcells activates the innate immune response, such as theactivation of Toll-like receptors (TLR). In the heart, TLR2and TLR4 are perhaps involved in the host response tomyocardial infarction [72]. The activation of TLR initiatesthe imbalance of TLR-induced cytokines regulation [73].

AtherogenesisAtherosclerosis is a chronic inflammation in the bloodvessels, resulting in the buildup of fatty streaks, and with

time, atherosclerotic plaques. Obesity, insulin resistanceand high blood pressure are the risk factors for the dis-ease. The gut microbiota has been suggested to play a sig-nificant role through its processing of phosphatidylcholinein the diet, leading to pro-atherogenic metabolites in [74].Atherosclerosis has been shown to have an inflammatorycomponent, and pro-inflammatory adipokines may be im-portant mediators of atherogenesis in abdominally obesesubjects [65]. The anti-atherogenic actions of adiponectinappears to be multifactorial, including inhibition of endo-thelial activation, reduced conversion of macrophages tofoam cells and inhibition of the smooth muscle prolifera-tion and arterial remodelling that characterizes the devel-opment of the mature atherosclerotic plaque [75].

Diabetes, insulin resistanceSteppan et al. described links between obesity and diabetesby hormone named resistin (for resistance to insulin), aunique signaling molecule, adipocytes secrete [76]. It wasdemonstrated the improvement of lipid metabolism in thecase of probiotic consumption [77]. For example, themodulation of gut microbiota, e.g. dietary intervention witholigofructoses, reduced metabolic endotoxemia andthe cecal content of LPS, improved glucose intolerance, in-sulin sensitivity and decreased body weight gain in bothhigh-fat fed and ob/ob mice [78].In models of diabetes, probiotic intervention has been

examined for its ability to impact on metabolic biomarkersof disease. Tabuchi et al. showed that Lactobacillusrhamnosus GG improved glucose tolerance in thestreptozotocin-induced rat model of diabetes possibly dueto the prevention of insulin secretion decrease [79]. Studiesusing the traditional Indian yoghurt, dahi, supplementedwith probiotic strains of Lactobacillus acidophilus andL. casei have shown that this product can improve markersof diabetes, including hyperglycemia, and hyperinsulinemiain high-fructose-induced rat models of diabetes [80,81].For instance, it improves insulin sensitivity and glycemic

control [82], and levels of this adipokine correlate positivelywith levels of HDL cholesterol and inversely with TGor PAI-1 [83].Type 1 diabetes (T1D) is considered as a debilitating

autoimmune disease that results from T cell-mediateddestruction of insulin-producing beta cells. The innate im-mune system is another factor that probably influences thecomposition of the intestinal microbiota. This is best illus-trated by a study showing that diabetic mice deficient in theinnate signaling molecule MyD88 are protected from thedevelopment of type 1 diabetes [65,84].

InflammationInflammation is a key feature of obesity and type 2 diabetes[85], being a source of oxidative stress, which is also impli-cated in the development of atherosclerosis. Elevated levels


of plasma and urinary F2-isoprostanes have been foundin a number of inflammatory diseases [65,86]; increasedproduction of reactive oxygen species may also enhancethe inflammatory response by activating redox-sensitivenuclear transcription factors such as AP-1 and NF-κB.These transcription factors are essential for the inducibleexpression of genes associated with immune and inflamma-tory responses, including cytokines, cell adhesion moleculesand inducible NO synthase. Thus, the pro-inflammatoryand pro-oxidant effects of increased adiposity represent apotential link between obesity and CVD. F2-isoprostanesare prostaglandin-like products of the free radical-catalyzedperoxidation of arachidonic acid. They are formed in situesterified to phospholipids and are released into plasma byphospholipases [87].The non-steroidal anti-inflammatory drugs as diclofenac

are associated with the formation of reactive metabolitesand hepatotoxicity [88]; the potential risks of non-steroidalanti-inflammatory drug for obesity development is promis-ing but not yet studied.

Atopic diseases and obesityMost of the studies point out that obesity is capable of in-creasing the prevalence and incidence of asthma, althoughthis effect appears to be modest. The treatment of obeseasthmatics must include a weight control program [89].Obesity is capable of reducing pulmonary compliance,

lung volumes, and the diameter of peripheral respiratoryairways as well as affecting the volume of blood in thelungs and the ventilation-perfusion relationship. Further-more, the increase in the normal functioning of adipose tis-sue in obese subjects leads to a systemic pro-inflammatorystate, which causes a rise in the serum concentrations ofseveral cytokines, the soluble fractions of their receptorsand chemokines. Many of these mediators are synthesizedand secreted by cells from adipose tissue and receive thegeneric name of adipokines, including IL-6, IL-10, eotaxin,tumor necrosis factor-alpha, transforming growth factors-beta1, C-reactive protein, leptin and adiponectin.According to the hygiene hypothesis, it asserts that the

increase in the prevalence of atopic disease is related toreduced exposure to microbes at an early life [40-42].According to the study by Shinkai et al. [90], type-2

immunity requires orchestration of innate and adaptiveimmune responses to protect mucosal sites from pathogens.Dysregulated type-2 responses result in allergy or asthma.T helper 2 (T(H)2) cells elaborate cytokines, such as IL-4,IL-5, IL-9 and IL-13, which work with toxic mediators ofinnate immune cells to establish environments that areinhospitable to helminth or arthropod invaders.The importance of T(H)2 cells in coordinating innate

immune cells at sites of inflammation is not known.Here, we show that polarized type-2 immune responsesare initiated independently of adaptive immunity. In the

absence of B and T cells, IL-4-expressing eosinophils wererecruited to tissues of mice infected with the helminthNippostrongylus brasiliensis, but eosinophils failed todegranulate. Reconstitution with CD4 T cells promotedaccumulation of degranulated IL-4-expressing cells, but onlyif T cells were stimulated with cognate antigen. Degranula-tion correlated with tissue destruction, which was attenuatedif eosinophils were depleted. Helper T cells confer antigenspecificity on eosinophil cytotoxicity, but not cytokine re-sponses, so defining a novel mechanism that focuses tissueinjury at sites of immune challenge [40,73,89-91].The cytokine interleukin-17 (IL-17) has received

considerable attention since the discovery of a distinctCD4(+) T helper (T(H)) cell subset that produces it,known as the T(H)17 cell subset. Despite the fact thatmost of the recent literature describes IL-17 as a T cell-secreted cytokine, much of the IL-17 released during an in-flammatory response is produced by innate immune cells.In this review, we explore the many innate immune cellpopulations that are an early source of IL-17 in responseto stress, injury or pathogens. These early sources havebeen shown to have a central role in the initiation ofIL-17-dependent immune responses, even before thefirst CD4(+)T cell sees its cognate antigen and initiatesthe T(H)17 cell developmental program [90,91].Both systemic and myeloid tissue-specific A(2B) R

deletion significantly decreased pulmonary inflamma-tory cell recruitment, airway mucin production andpro-inflammatory cytokine secretion after final allergenchallenge in sensitized mice. A(2B) R deficiency resultedin a dramatic reduction on Th2-type airway responseswith decreased pulmonary eosinophilia without augment-ing neutrophilia and decreased lung IL-4, IL-5 and IL-13production. Pro-inflammatory TNF-α, IFN-γ and IL-17secretion were also reduced in systemic and myeloidtissue-specific A(2B) R deletion mouse lines [92]. ThisTh2-type dysfunction in bronchial asthma inclines to useimmunocorrection that can be achieved with probioticsbased on Gram-positive microorganisms [93,94].

Infection-related metabolic conditionsIt was speculated that adenovirus 36 (Adv36) not onlyinfects humans but also can make them obese [95]; studiesin humans and experiments in animals supported thishypothesis. There were illustrated extensive interrelationsamong virus action, cellular oxidative stress, gene damage,multiple immune pathways and proteomic changes indiabetes mellitus, cancer and many chronic disordersdevelopment; many of them are also related to HPV infec-tion [96,97]. On the other hand, the obesity may inducethe T cell response in virus infection [98]. Patients withincreased BMI and adiposity also present a higher inci-dence of surgical site infections with increased risk ofwound complications [85,99].


Gender and obesityFindings showing women’s differential metabolic re-sponses have suggested a gender effect on biochemical-endocrinological patterns, metabolic mechanisms andrisk factors, emphasizing the importance of more gender-specific prevention strategies [10]. This is especially relevantvs environmental changes and the obesogenic epidemic,with women’s lead in earlier and higher obesity ratesand related disease risk, though with manifestation mostlydelayed to menopausal age. Estrogen receptors (ER) arewell-known regulators of several aspects of metabolism,including glucose and lipid metabolism, and impairedestrogen signaling is associated with the developmentof metabolic diseases [10,100]. Here, ERα seems to playa protective role in insulin and glucose metabolismthrough effects on the liver, adipose tissue, muscle, andpancreatic β cells and on central regulation of food in-take and energy expenditures. ERβ, on the other hand,has the potential to negatively influence insulin and glu-cose metabolism by impairment of adipose tissue func-tion. The onset of menopause dramatically increases therisk for women to develop disease states coupled to themetabolic syndrome, such as obesity, CVD, and type 2diabetes [10]. The endometrial receptor status beingstrongly associated with metabolic mechanisms contrib-ute the diagnostic algorithm as potential biomarkersfor pathogenetic therapy. Thus, in determining rela-tionships in the endometrial receptor system, each in-dividual pathological pattern of receptors and theirrelationship further defines personalized pathogenetictactics tailored to the person [100].

Hyperuricemia, goutHyperuricemia, which is strongly associated with obesityand metabolic syndrome and can predict visceral obesityand insulin resistance, might be partially responsible forthe pro-inflammatory endocrine imbalance in the adiposetissue, which is an underlying mechanism of the low-grade inflammation and insulin resistance in subjects withthe metabolic syndrome [101] and is discussed to be in-volved in the mechanism of MSG metabolism. Gutman in1973 [102] expressed the hypothesis that, possibly second-ary to altered glutamate catabolism, glutamine apparentlyis overutilized for urate overproduction by the liver andunderutilized for reduced renal ammonia formation. Thekidneys, modulating urinary uric acid excretion, sustainthe hyperuricemia. In these considerations of the possiblerole of glutamine, another factor should now be taken intoaccount, namely, the hyperglutamatemia of primary gout.Pagliara and Goodman suggested that in gout, the im-paired catabolism is due to a partial deficiency of glu-tamate dehydrogenase; gouty patients had raised levelsof plasma glutamate [103]. Certain foods and food ad-ditives are used along with monosodium glutamate, or

MSG, to enhance the flavor of bland food, and containpurines, which are directly metabolized into uric acid,as guanylate (E626, E627, E628 and E629), inosinate(E630, E631, E632 and E633), and their compoundsribonucltides (E634 and E635) are metabolized to purines.More studies are required to establish the links with foodadditives and crystal deposition diseases, prior to gout.Gout is characterized by the deposition of reversible

monosodium urate (MSU) crystals and occurs as a con-sequence of hyperuricemia [104] which induces inflam-matory arthritis [105] and nephropathy [106] and hasrisen over the last decade. Dr. Veronique Vitart, fromthe Medical Research Council Human Genetics Unit at theUniversity of Edinburgh, researcher of hyperuricemia gen-etics said: ‘Abnormal levels of uric acid have been associatedwith various common diseases and conditions, but causalrelationships are not always clear. Gaining insight into thegenetic components of uric acid levels offers a very usefultool to tackle these issues and to further our understandingof these conditions.’ In the study by Köttgen et al., including110,347 individuals from 48 studies were suggested and28 genome-wide significant loci associated with serumurate concentrations were identified. Those alleles asso-ciated with increased serum urate concentrations werealso associated with increased risk of gout. The modulationof urate production and excretion by signaling processesthat influence metabolic pathways, such as glycolysis andthe pentose phosphate pathway, seems to be central path-ways including the genes from the newly identified associ-ated loci. These findings may have implications for furtherresearch into urate concentration, lowering drugs to treatand prevent the common inflammatory arthritis gout [107].Advanced imaging modalities including MRI, ultrasound

(US), CT and dual energy CT have important applicationsin gout. US and MRI also reveal the severity of inflam-mation within and adjacent to the joint and can cap-ture information about the composite, vascular natureof many tophaceous deposits [104,108]. According toour recent data [109], ultrasound can be an effectivemethod for early detection of liver and kidney involvementin gout patients with sensitivity, specificity, positive andnegative predictive value and accuracy; the gout involve-ment of liver and kidneys using complex ultrasonographydiagnostic criteria were 92.6%, 84.4%, 80%, 95% and 91.9%respectively. We suggested the integrated index calculatedby suggested mathematical model according to which theprocess (disease progression) is described by the primaryindicators (biomarkers) that with output rate are stochasticin nature and presented as statistical information. A specialalgorithm for processing statistical data could be reliable fordisease staging and control treatment follow up. Werecommended to create the system for complex evaluationof biomarkers using suggested mathematical model basedfrom patient medical records for prediction, personalized


treatment and prevention of gout in relation to metabol-ism and obesity that may be applicable in still existingclosed medical system, obtaining relevant extensive data.

Immune pathwaysThe ability of probiotics, which affects the relevant Toll-likereceptors (TLRs), can promote effective immune responseand the initiation of an effective immune defense [73].Gram-positive bacteria affect the formation of T and B cellimmune response by altering products primarily; IFN-γand IL-12 are required for differentiation of T helper cellsinto Th1 subpopulation direction. However, probioticpreparations are capable of activating both (Th1 and Th2)lymphocyte subpopulations, which provide a balance ofcytokine production. Immunomodulatory activity of pro-biotic preparations is most important to identify the goodswhich induced opposite cytokines IL-10 or IL-12 in exper-iments in vitro when stimulating macrophage cells. Theimmune response against infectious diseases of probioticdrugs is activated due to the ability to balance the body’simmune status at the level of receptor-ligand interactions.Probiotic preparations are the agonists TLR-2, and thepresence of common protein adapter molecules (TIRAP),MyD88 for TLR-2 and TLR-4 to influence the signalingpathways of cytokine production under the influence ofthe ligands. Inhibition of TLR2-induced signaling, influ-enced by lactobacilli via adapter Mal/MyD88, can leadto partial inhibition of TLR4 signal, accompanied by de-creased production of pro-inflammatory cytokines. Abilityto influence signaling pathways of cytokine productionopens new perspectives for the creation of probiotic prep-arations with anti-inflammatory properties.According to our recent data [110], daily oral admin-

istration of strains L. rhamnosus V® or L. rhamnosusLB3 IMB B-7038 (1 × 106 cells / mouse) for 4 days andinfected Staphyloccous aureus 8325 mice in a dose(5 × 108 CFU/mouse) LD50 was accompanied by a reduc-tion in the mortality of animals. The introduction of lacticacid bacteria to the animals infected with S. aureus allowedincreased functional activity of phagocytic system andthe normalization parameters of cellular immunity ac-tivation and production of interferon-γ and IL-12 indifferent periods of observation. However, decreasedproduction of IL-4 indicates the ability of probiotic strainsto balance the immune response in the upward cytokineproduction by Th1-type, which guide the developmentof the immune response to cell type. The introductionof lactic acid bacteria accompanied the strengthening ofthe ability of splenocytes to produce IFN-α and IFN-γin response to adequate stimulation. Strengtheningbiocide activity of macrophages and cytotoxicity naturalkiller under the influence of experimental strains leadsto a significant increase of elimination S. aureus-infectedkidneys of animals.

These data suggest that lactic acid bacteria maydynamically modulate the mechanisms of innate andadaptive immunity by maintaining the balance betweenTh1 and Th2 lymphocytes, which allows us to considerthem as immunomodulatory drug selective action [108].

Associations with neurodegenerative, musculoskeletaldiseases and painInterferon-b is an established treatment for patients withmultiple sclerosis (MS), but its mechanisms of action arenot well understood [111]. Viral infections are a knowntrigger of MS relapses. Toll-like receptors (TLRs) are keycomponents of the innate immune system, which senseconserved structures of viruses and other pathogens[73]. The upregulation of TLR7 in pDCs and a conse-quently increased activation of pDCs by TLR7 ligandsrepresents a novel immunoregulatory mechanism ofinterferon-b. Derkow et al. hypothesized that this mechan-ism could contribute to a reduction of virus-triggered re-lapses in patients with MS [111].Many studies clearly suggest that TLRs, acting through

MyD88-dependent and/or independent mechanisms,induce pro-inflammatory signals for the developmentof myopathy in skeletal muscles. Thus, the emergingparadigm indicates that not only innate and adaptiveimmune mechanisms but also intrinsic defects in myo-pathic skeletal muscle contribute to muscle weakness anddamage such as myositis. The muscle microenvironmentis complex, consisting of active interactions occur betweeninnate, adaptive, metabolic and homeostatic pathways inthe muscle in these diseases [112].Acute exposure of skeletal muscle to elevated levels

of FFA induces insulin resistance, whereas chronic ex-posure of the pancreas to elevated FFA impairs β-cellfunction [113,114]. Obesity-related postural mechanism,neuromuscular networks and pain muscle and immune-neurodegenerative relationships are still unclear and sub-ject for further studies [115].

Vasospasm, congestion and obesityEndothelial dysfunction (ED) induced by obesity is animportant risk factor that impairs blood flow controls invarious organs. Obesity impairs microvascular function inseveral ways. ED results from an imbalance between NOand endothelin (EDN), being the regulators of vascularfunction. Obesity-induced ED is associated with decreasedNO production due to impaired endothelial NO synthaseactivity and expression and increased production of super-oxide anion and the endogenous NOS inhibitor ADMA,together with increased vasoconstrictor factors, such asendothelin-1 and sympathetic nerve activation [116].Genetic variants in NO synthase and EDN isoforms

and its receptors (EDNRA and EDNRB) appear to ac-count for important components of the variance in ED,


particularly when concurrent risk factors such as obes-ity exist. Analysis of genotype-phenotype interactionsis critical for the formulation of the potentially alteringpredisposition to cardiovascular diseases [117]. NOsynthase and endothelin genes are related with manydiseases, namely, asthma [118] and renal failure [119],that make them the potential biomarkers of numeralobesity collateral pathologies.Meyer et al. found that in the aorta of obese mice,

perivascular adipose potentiates vascular contractilityto serotonin and phenylephrine, indicating the activityof a factor generated by perivascular adipose, which wedesignated as ‘adipose-derived contracting factor’ (ADCF)[120]. Inhibition of cyclooxygenase (COX) fully preventedthe ADCF-mediated contractions, whereas COX-1 orCOX-2-selective inhibition was only partially effective.By contrast, inhibition of superoxide anions, NO syn-thase, or endothelin receptors had no effect on ADCFactivity [120].Congestive mesenteric [121] and/or pelvic syndromes

(ovarian vein reflux) [122] are the condition characterizedby the presence of venous congestion and varicose veinsin the mesenteric and pelvic region and play importantrole for dysregulation of intestinal and systemic micro-circulation mechanisms leading to ED in overweight pa-tients and have potential risk for the development ofmany vascular and hormonal disorders related to obesity.In obese individuals, the mixed meal drink decreases thebaseline skin perfusion and causes acetylcholine-mediatedvasodilation but has no effect on the capillary density.Obese individuals had impaired acetylcholine-mediatedvasodilation after meal ingestion. The latter findings areconsistent with impaired postprandial microvascular func-tion in obesity [123].Peripheral microcirculation assessment might be con-

sidered to support a supplementary information forobese patients particularly for vasospasm assessment[124], including laboratory biomarkers and capillaroscopy[125]; Doppler techniques for assessment of vascular re-sponses following cuff-induced arterial occlusion allowdeterminations of the kinetics of post-ischemic reperfu-sion and provides an accurate reporter of NO-mediatedphysiological recruitment [117].

Nanotechnologies - the challenge for advanced diagnosis,treatment and preventionAdvances in nanoscience, nanotechnology and nanomedi-cine lead to the construction of new materials and devicesfor various scientific and therapeutic purposes whichare applicable in molecular diagnostics, nanodiagnosticsand improvements in the discovery, design and deliveryof drugs, including nanopharmaceuticals. The applica-tion of nanoparticles allowing the combination of ther-apy and diagnosis, known as theranostic, has received

increasing attention in biomedicine [126]. Pharmaco-logical, pharmaceutical and toxicological aspects of theapplication of nanoparticles in biomedical purposes stillremain poorly understood. While oxidative stress hasbeen postulated as one of the main physiopathologicalhallmarks of most of chronic diseases, the nanoparticlesof gold [126,127] and cerium dioxide [118,119] were re-ported as strong agents against oxidative damage hav-ing anti-aging activity. Nanoparticles of cerium dioxide,considering its UV-shielding effect, antiviral, antibacterial,antifungal activity, cardioprotective, neurotrophic, hepato-and nephroprotective and anti-aging effect, have potentialfor various biomedical applications [126-129]. Treatmentwith nanoceria has supplementary perspectives in gyne-cology and reproductive medicine and also in women withhormone-associated obesity which results from the increasein the number of oocytes in follicles, increase in the num-ber of oocytes at metaphase I and metaphase II, increase inthe number of living granulosa cells and decrease in thenumber of necrotic and apoptotic cells [128,129].

Potential economical impactsObesity as a condition associated to many pathologies ac-counts for the burden related to the treatment of these pre-ventable diseases (about €59 billion a year in EU; US$71.1billion in the USA). The combined medical costs attrib-utable to obesity and overweight are projected to doubleevery decade and will account for 16% to 18% of thetotal US health care expenditure by 2030 [130]. Thus,considering integrative medical approach against obes-ity within the PPPM paradigm should lead to significanteconomic benefits.

Education for preventive measuresEducational programs and individual preventive facilitiesare the important tasks for the PPPM concept in metabolicdisorder early risk factors detection and early obesityenvironment programming. A number of potential effect-ive plans can be implemented to target built environment,physical activity and diet. Primary or secondary preventionof obesity and these strategies are more effective inchildren than in adults [131]. These strategies can beinitiated at home and in preschool institutions, schools orafter-school care services as natural setting for influencingthe diet and physical activity and at home and work foradults. Dissemination of information is necessary in or-der to popularize dietary recommendations, screeningprograms and patient participation approaches againstrisk factors including obesity, fat diet, diabetes, womenhealth and family history. The material for dissemin-ation and lecturing should be culture specific and eth-nically standardized to the socio-economical aspects ofthe targeting population (well translated, to be easilyunderstood) in order to facilitate the work. Development


and implementation of linguistically validated evidence-supported questionnaires are required to assessmentconditions specific to obesity which is tailored to theperson. Support of preventive educational activity withlong-term commitment of private and public fundingprograms is required.

Consolidation of the PPPM conceptPersonalized medical approachAvoiding adverse additive and designing person-relatedprobiotic strains are important impacts to personal-ized dietology.

Predictive medical approachTranslating obtained data on animal model to humanorganism may allow to consider consumption of theproducts containing MSG, especially in early age, as apredictive value for obesity and metabolic syndromedevelopment. Developing the panel of obesity assess-ment biomarkers is an important point.

Preventive medical approachTranslation of the obtained data on animal model to humanorganism may allow to consider diet correction with pro-biotics within early obesity environment programming asa strong preventive measure against obesity epidemic.

Expert recommendationsConclusionThe introduction of monosodium glutamate to newbornrats causes obesity in adulthood. Periodic administrationof probiotic blends to rats that received MSG in neo-natal period prevented the development of obesity.

Future outlooks and recommendationsFurther studies including sufficient cohorts of volunteersare necessary to translate model data of probiotic efficacyto human population as well as conduction of epidemio-logical studies for obtaining evidence regarding adverseeffect of particular food additives.We also suggest the further studies regarding obesity

and metabolic disorders inducible by expression of genesassociated with obesity environment, dietary additives,immune and inflammatory responses, and develop and testpromising nanomaterials (e.g. nanoceria) for prospect ofcomplex impact to gastrointestinal microbiota and motility.Create the relevant models to study microbiota related to

specific process (diabetes, gout, hepatitis, cancer, CVD, etc.).Obtained results may indicate the effectiveness of probiotictherapy to prevent obesity in human based on personalizedmicrobiota additives. To achieve the personalized ap-proach, the development and application products man-ufactured from own strains of organism are consideredpromising. The potential alternative for probiotics might be

the suggested lysates of probiotic strains that also exhibitimmunomodulatory activity.After approval, development of safe and effective person-

related medications/additives with future clinical test-ing should be initiated to implement results for routinepractice.With the concluding points, we can formulate the

following proposals (expert recommendations):

1. For the European Union (EU): create aninternational project to study the effects ofprobiotics for the implementation of evidence-basedpersonalized dietology against obesity and metabolicsyndrome.

2. For Ukraine: participate in the project in partnershipwith EU to follow up experimental and clinicaltrials and involve related institutions and centresto the study.

AbbreviationsCFU: colony-forming units; CVD: cardiovascular diseases; FFA: free fatty acids;HDL cholesterol: high-density lipoprotein cholesterol; LDL: low-densitylipoprotein; MSG: monosodium glutamate; PPPM: predictive preventive andpersonalized medicine; VLDL: very low-density lipoproteins; WHO: WorldHealth Organization.

Competing interestsThe authors declare that they have no competing interests.

Authors' contributionsSOA, VOV and FTM performed experiments and statistical analysis ofobtained data and prepared the article. BTV did the organization, literaturereview and analysis of the study. LLM performed experiments and analysis ofthe study and prepared the article. RVB participated in the analysis of thestudy, did the literature review in part of the discussion, formulatedprospects and performed the final article drafting. MYS did the organizationand analysis of the study and prepared the article. All authors read andapproved the final manuscript.

Authors' informationSOA, VOV, FTM, Ph.D., D.Sci., and Professor BTV, Ph.D., D.Sci. are researchers ofSRL ‘Pharmacology and Experimental Pathology’, Department of Biologicaland Biomedical Technology, ESC ‘Institute of Biology’, Taras ShevchenkoNational University of Kyiv. Professor LLM, Ph.D., D.Sci. is a researcher inInteferon Department of Zabolotny Institute of Microbiology and Virology,National Academy of Sciences of Ukraine. RVB, M.D., Ph.D. is a medicaldoctor in the Clinical Hospital ‘Pheophania’ of the State Affairs Department,researcher of the Inteferon Department of Zabolotny Institute ofMicrobiology and Virology, National Academy of Sciences of Ukraine, andNational Representative of the European Association for Predictive,Preventive and Personalised Medicine (EPMA) in Ukraine. Professor MYS, Ph.D., D.Sci. is a corresponding member of the National Academy of Sciences ofUkraine and the director of the Inteferon Department of Zabolotny Instituteof Microbiology and Virology, NAS of Ukraine, Kyiv, Ukraine.

AcknowledgmentThe study was conducted with the support of the State Agency on Science,Innovations and Informatisation of Ukraine. We acknowledge the kind helpof the EPMA journal editorial team and BioMed Central team in improvingthe text of the article.

Author details1Taras Shevchenko National University of Kyiv, Volodymyrska Str., 64/13, Kyiv01601, Ukraine. 2Zabolotny Institute of Microbiology and Virology, NationalAcademy of Sciences of Ukraine, Zabolotny Str., 154, Kyiv 03680, Ukraine.3LCL ‘DIAPROF’, Svitlycky Str., 35, Kyiv 04123, Ukraine. 4Clinical Hospital


‘Pheophania’ of State Affairs Department, Zabolotny str., 21, Kyiv 03680,Ukraine.

Received: 22 August 2013 Accepted: 26 December 2013Published: 13 January 2014

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doi:10.1186/1878-5085-5-2Cite this article as: Savcheniuk et al.: The efficacy of probiotics formonosodium glutamate-induced obesity: dietology concerns andopportunities for prevention. The EPMA Journal 2014 5:2.

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